2. Academic Validation
  3. Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis

Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis

  • Pharmacol Res. 2021 Feb;164:105367. doi: 10.1016/j.phrs.2020.105367.
Mengzhu Zheng 1,  Canrong Wu 1,  Kaiyin Yang 1,  Yueying Yang 2,  Yang Liu 2,  Suyu Gao 2,  Qiqi Wang 2,  Chen Li 2,  Lixia Chen 3,  Hua Li 4
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
  • 2 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 3 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: syzyclx@163.com.
  • 4 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China. Electronic address: li_hua@hust.edu.cn.
PMID: 33307221 DOI: 10.1016/j.phrs.2020.105367
Abstract

Accelerated glucose metabolism is a common feature of Cancer cells. Hexokinase 2 (HK2) as the rate-limiting Enzyme catalyzes the first step of glucose metabolism. It is overexpressed in most of the human cancers and has been a promising target for Cancer therapy. Here, we report a novel selective HK2 inhibitor Benitrobenrazide (BNBZ), with nanomolar inhibitory potency. In vitro, BNBZ directly binds to HK2, induces Apoptosis, and inhibits proliferation of HK2-overexpressed Cancer cells. BNBZ also significantly inhibits the glycolysis of SW1990 cells by targeting HK2. The knockdown or knockout of HK2 expression in SW1990 cells can reduce their sensitivity to BNBZ. Additionally, oral administration of BNBZ can effectively inhibit tumor growth in SW1990 and SW480 xenograft models. In general, BNBZ significantly inhibited glycolysis and Cancer cell proliferation in vitro and in vivo by directly targeting HK2 with high potency and low toxicity, and can be developed as a novel HK2 small-molecule candidate drug for future Cancer therapeutics.

Keywords

Cancer metabolism; Cancer therapeutics; Glycolysis; Hexokinase 2.

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